Microorganisms, either singly or as a group, are generally accepted to be the primary etiological agents responsible for the initiation of dental caries, periodontal disease, and dental infections. In the healthy mouth, the number of microorganisms may not reach the threshold level required to initiate oral disease (the threshold may be different both for different micoorganisms in a given flora and for different individuals), in large part because of the regulation by the immunoglobulins and by a series of proteins commonly described as the non-immune host defense factors (for example, lysozyme, lactoperoxidase, lactoferrin, histidine-rich polypeptides) (Mandel, "Microbial Aspects of Dental Caries", 3, pp. 589-866, 1976; Mandel, Amer. Sci., 67, pp. 680-688, 1979; Pollock, et al., Infect. Immun. 44, pp. 702-707, 1984). However, when the delicate belance between host and pathogen is tipped in favor of the microbes, human infection can result in the susceptible host (Mackowiak, New Eng. J. Med., 298, pp. 21-26 and 83-87, 1978).
In the oral cavity, a number of microbial species make up the dental plaque; however, only some of these microbes become pathogenic and initiate dental caries and periodontal disease when their numbers rise above the threshold level for disease. In the case of dental enamel (cavities of the smooth and interproximal areas of the teeth) and fissure (cavities of molar teeth) caries in both children and adults, the pathogenic organisms have been fairly conclusively shown to be specific immunological serotypes of Streptococcus mutans and various species of Lactobacilli (Loesche, et al., Infect. Immun., 46, pp. 765-772, 1984). Both S. mutans and the Lactobacilli are the most acidogenic (highest production of acid) and aciduric (able to survive at low acid pHs of 4 to 5.5 with continued production of acid) microbial species in the dental plaque. In the case of adult root caries (cavities located in exposed areas of dentin on the roots of the teeth), pathogenic species have not been conclusively identified; however, Actinomyces species have been suggested since they do produce sufficient acid for dissolving the dentin (usually at pHs of 5.5 or greater) and more importantly are one of the major members of the supragingival (where the gum margin meets the tooth surface) bacterial floras (Moore, et al., Infect. Immun., 46, pp. 1-6, 1984). In the case of gingivitis or mild periodontal disease which, in turn, can lead to more advanced disease, Actinomyces species such as A. viscosus and A. naeslundii may be causative agents as may be Fusobacterium nucleatum (Moore, et al., Infect. Immun., 46, pp. 1-6, 1984; Moore, et al., Infect. Immun., 42, pp. 510-515, 1983). In more advanced severe periodontal disease, Fusobacterium nucleatum has been suggested to be the major pathogen of the subgingival flora (DiRienzo and Rosan, Infect. Immunity, 44, pp. 386-393, 1984; Moore et al., Infect. Immun., 38, pp. 1137-1148, 1982).
There are a number of approaches to the treatment of dental caries which is known to be multifactorial in nature. For example, it is well documented that limiting the amount of ingested sugar and thus the amount of acid produced can reduced the incidence of cavities. Unfortunately, such self-limitation in most population groups usually remains modest and is easily reversible. For this reason, caries preventive and treatment measures such as (i) mechanical debridement of the teeth with toothpastes or rinses, etc., to remove bacterial plaque, (ii) remineralizing and enamel fortifying solutions, (iii) over-the-counter dental products containing plaque adherence inhibitors, (iv) dental products containing agents which raise/or maintain the pH of the saliva or dental plaque, and (v) over-the-counter dental products containing antibacterials have all come into use. To date, the most important caries preventive measure is fluoride in the form of fluoridated water, fluoridated toothpastes and rinses, and fluoridated-supplemented vitamins and foodstuffs. Fluoride is thought to act by fortifying the enamel, by maintaining the pH and by serving as an antibacterial agent (Brown and Konig, "Cariostatic Mechanisms of Fluoride", pp. 1-327, 1977), but under normal treatment it reduces cavities only to the extent of about 25 to 30%. Long-term disciplined supplementation of fluoride in the form of fluoride rinses has resulted in caries reduction of greater than 50% in school children (Leverett, Science, 217, pp. 26-30. 1982). However, in the public view, there is a rising concern over the possibility of fluoride toxicity because of the need for continuous daily rinsing at reasonably high fluoride concentrations.
To date, the antibacterial agents (including fluoride) used for the treatment of dental caries rely on either a bacteriostatic (growth inhibition) or bactericidal (inhibition of the multiplication of the bacteria) activity. Most of these agents therefore suffer from the fact that the bacteria can both reverse these effects and can still metabolize sugars to produce acid which in turn can destroy the teeth. It would be desirable to overcome these disadvantages in achieving as the antibacterial effect, bacterial cell lysis. Under bacteriolytic conditions, the cariogenic pathogens are destroyed irreversibly and no acid can therefore be produced.
Bicarbonate, fluoride, chloride and thiocyanate are the major monovalent anions normally present in human saliva (Pollock, et al., Archs. Oral. Biol. 26, 711-716, 1981). The concentrations of each of these anions have been observed to vary with salivary flow rate and with duration of collection at fixed flow rates (Dawes Archs., Oral. Biol., 14, pp. 277-294, 1969; Jenkins, "The Physiology and Biochemistry of the Mouth", 4th. Edition, pp. 284-359, 1978; Kreusser, et al., Eur. J. Clin. Invest., 2, pp. 398-406, 1972). Natural, normal physiologic concentrations in submandibular, parotid and mixed human salivas range for bicarbonate from 1 to 60 millimolar, for chloride from 10 to 50 millimolar and thiocyanate from 0.5 to 4.5 millimolar (Jenkins, supra.). After a mouth rinse for two minutes with 0.2% sodium fluoride, salivary fluoride concentrations were found to average 36 millimolar (Brunn, et al., Community Dent. Oral Epidemiol., 10, pp. 124-129, 1982). At neutral pH (or at pHs at least greater than 6.0), all four anions (when supplied as inorganic salts) will activate cell lysis (Pollock, et al., Archs Oral Biol., 26, 711-716, 1981; Wilkens, et al., Infect. Immun., 38, 1172-1180, 1982) but at acidic pHs of 5 or 4 (corresponding to the pHs of the carious lesion) only bicarbonate when used alone will cause the cariogenic pathogens to lyse (Pollock, et al., Archs. Oral. Biol., 28, 865-871, 1983; Pollock, et al., Infect. Immun., 45, 610-617, 1984). In the human mouth, the amount of bicarbonate secreted by a individual has been proposed to be of critical importance to dental caries. We propose that this is not so much due to the buffering capacity of the bicarbonate anion as suggested by other investigators (Agus and Schamschula, Caries Res., 17, 139-144, 1983; Pickerill, "The Prevention of Dental Caries and Oral Sepsis", 1912; Hubbell, Am. J. Physiol., 105, pp. 436-442, 1933; Ericsson, Acta Odont. Scand., 11, pp. 179-194, 1954) but rather to the ability of bicarbonate to activate bacteriolysis of lysozyme-protease damaged microbes as suggested originally by us (Pollock, et al., Archs. Oral Biol., 26, 711-716, 1981; Goodman, et al., J. Bacteriol., 146, 764-774, 1981). It should be pointed out that the inorganic salts of divalent anions such as carbonate or phosphate, will not activate cell lysis for biochemical reasons discussed in our publications (Pollock, et al., "Saliva and Dental Caries", pp. 429-447, 1979; Goodman, et al., J. Bacteriol., 146, 764-774 (1981).
Heretofore, use of combinations of these inorganic monovalent anions (preferably as their sodium salts) for the lysis of oral pathogens, particularly those like S. mutans and Lactobacilli with known cariogenic potential has not been proposed. Although these salts have been combined together in previous formulations, in many instances these combinations are only incidental to the formulations proposed. For example, Delany, et al., (Patent 3,937,804) use fluoride as their anti-caries agent but make no anti-caries claims for bicarbonate which is used at very high salt concentrations to give the consumer a clean mouth. Or for example, Pader, et al. (Patent 4,150,151) uses sodium chloride as an electrolyte and flavoring agent while proposing an anionic surfactant mouthwash which may include fluoride. In both of these examples, no claim is made for the combination of these inorganic salts as lytic agents for the elimination of pathogenic organisms associated with dental caries (and periodontal disease). In one patent by Weisz (3,975,514), a fluoride mouthwash composition was proposed in which both chloride and an anionic surface active wetting agent were minor components. It was stated that the ionic surface active agent plus the sodium chloride provided an enhancing antibacterial potential of the fluoride.
Clinical studies have shown that marked caries reduction can be obtained by bicarbonate-phosphate or bicarbonate-phosphate-fluoride combinations mixed into the dietary sugar of rats (Luoma, et al., Caries Res., 4, pp. 332-346, 1970). These studies have been followed by experiments in a controlled population of institutionalized mentally handicapped children. The results have shown that the inclusion of fluoride and a bicarbonate-phosphate mixture in sweet sugar products of the children's diet produces caries arrestment after the first year (Luoma, et al., Scand. J. Dent. Res., 87, pp. 197-207, 1979). In these studies, Luoma added the bicarbonate fraction mainly to serve as the buffering agent while the phosphate component (a divalent anion) was added to satisfy the phosphate need of cariogenic bacteria in order to prevent the enamel phosphate from being utilized for the bacteria's metabolic need. Again, lysis of bacteria by the combination of fluoride and bicarbonate was not discussed so that clinical studies did not include a therapeutic anti-caries design based on an optimal lysis concentration range of these anions.